FVIII (fVIII) replacement therapy is the mainstay of the management of congenital hemophilia A in developed countries. This TRC-THD U54 application, entitled Biological Variation in Hemophilia, seeks to improve our understanding of inhibitor development and the underlying basis for phenotypic heterogeneity in the severe hemophilia A population. Additionally, it proposes novel approaches to translate basic discovery into preclinical models of inhibitor treatment and into clinical studies to test novel diagnostics predictive of the bleeding diathesis n severe hemophilia A. The most dreaded complication of fVIII replacement therapy is the development of inhibitory antibodies to fVIII (inhibitors), which occur in approximately 30% of individuals with severe and moderately severe hemophilia A. Additionally, fVIII inhibitors can occur in nonhemophiliacs, producing an autoimmune condition called acquired hemophilia A. Acquired hemophilia A is the most common autoimmune bleeding disorder involving the coagulation system. Patients with acquired hemophilia frequently present with severe, life- or limb-threatening bleeding that is difficult to manage. Individuals with hemophilia A are treated either with on-demand therapy to manage bleeding episodes or with prophylactic therapy to prevent bleeding. To limit the potential for the development of crippling arthropathy most patients receive prophylactic therapy. However, the frequency of infusions required to deliver prophylactic therapy frequently results in poor compliance. As a result, many individuals with hemophilia A in the United States are treated with on-demand therapy. Prophylactic therapy is very expensive, creating an economic burden to society. Severe hemophilia A, which is defined by a fVIII activity assay in which the level is less than 1% of normal, usually is diagnosed in the first year of life. Individuals with severe hemophilia A often have spontaneous bleeding, i.e., bleeding in the absence of overt trauma. However, there is considerable variability in the bleeding diathesis within the severe hemophilia A population. Currently, there are no diagnostic tests that can predict variability of bleeding. Identification of such diagnostics would guide the management of individuals with severe hemophilia A in early life, e.g., by identifying individuals in whom prophylaxis should be aggressively pursued to protect target joints. Even the best current situation, namely successful prophylactic therapy in an individual with congenital hemophilia A who is not inhibitor prone, does not represent a cure. Gene therapy continues to represent the best chance for cure of hemophilia A. Advances in hematopoietic stem cell (HSC)-based gene therapy for other congenital disorders, including adrenoleukodystrophy and severe combined immunodeficiency disease, and preclinical studies in a murine hemophilia A model at Emory University, suggest that a cure for hemophilia A, including inhibitor patients, is imminent. State-of-the-art management of hemophilia occurs in multidisciplinary treatment centers. The care of individuals with hemophilia from infancy through adult life requires a team of physicians and allied personnel to manage the evolution of issues that arise. Additionally, a hemophilia treatment center ideally includes an integrated basic, translational and clinical research program to provide ongoing advances in the management of hemophilia. There is an unmet need for more physician scientists to provide the specialized care and conduct research in hemophilia treatment centers. The investigators in this project are physician-scientists, clinical investigatos and molecular biologists in the Hemostasis/Thrombosis Program in the Aflac Cancer Center & Blood Disorders Service at Emory University who have broad expertise in hemophilia care and hemophilia research. The program represents a fertile environment for training the next generation of physician-scientists, clinical, and basic researcher in the management and research of hemostatic disorders